Isotretinoin

ISOTRETINOIN- isotretinoin capsule, liquid filled
Amneal Pharmaceuticals LLC

CAUSES BIRTH DEFECTS

no pregnant

DO NOT GET PREGNANT

CONTRAINDICATIONS AND WARNINGS

Isotretinoin must not be used by female patients who are or may become pregnant. There is an extremely high risk that severe birth defects will result if pregnancy occurs while taking isotretinoin in any amount, even for short periods of time. Potentially any fetus exposed during pregnancy can be affected. There are no accurate means of determining whether an exposed fetus has been affected.

Birth defects which have been documented following isotretinoin exposure include abnormalities of the face, eyes, ears, skull, central nervous system, cardiovascular system and thymus and parathyroid glands. Cases of IQ scores less than 85 with or without other abnormalities have been reported. There is an increased risk of spontaneous abortion, and premature births have been reported.

Documented external abnormalities include: skull abnormality; ear abnormalities (including anotia, micropinna, small or absent external auditory canals); eye abnormalities (including microphthalmia); facial dysmorphia; cleft palate. Documented internal abnormalities include: CNS abnormalities (including cerebral abnormalities, cerebellar malformation, hydrocephalus, microcephaly, cranial nerve deficit); cardiovascular abnormalities; thymus gland abnormality; parathyroid hormone deficiency. In some cases death has occurred with certain of the abnormalities previously noted.

If pregnancy does occur during treatment of a female patient who is taking isotretinoin, isotretinoin must be discontinued immediately and she should be referred to an Obstetrician-Gynecologist experienced in reproductive toxicity for further evaluation and counseling.

Special Prescribing Requirements

Because of isotretinoin’s teratogenicity and to minimize fetal exposure, isotretinoin is approved for marketing only under a special restricted distribution program approved by the Food and Drug Administration. This program is called iPLEDGE ® . Isotretinoin must only be prescribed by prescribers who are registered and activated with the iPLEDGE Program. Isotretinoin must only be dispensed by a pharmacy registered and activated with iPLEDGE, and must only be dispensed to patients who are registered and meet all the requirements of iPLEDGE (see PRECAUTIONS).

Table 1. Monthly Required iPLEDGE Interactions

Females of Reproductive Potential (FRP)

Male Patients, a nd Females

of Non-Reproductive Potential

(FNRP)

PRESCRIBER

Confirms patient counseling

X

X

Enters the two contraception

methods chosen by the patient

X

Enters pregnancy test

results

X

PATIENT

Answers educational questions

before every prescription

X

Enters two methods of contraception

X

PHARMACIST

Contacts system to get an authorization

X

X

DESCRIPTION

Isotretinoin USP, a retinoid, is available in 10 mg, 20 mg, 30 mg and 40 mg soft gelatin capsules for oral administration. Chemically, isotretinoin is 13-cis-retinoic acid and is related to both retinoic acid and retinol (vitamin A). It is a yellow to orange crystalline powder. The structural formula is:

chem structure
(click image for full-size original)

C20 H28 O2 Molecular Weight: 300.44

Each capsule contains the following inactive ingredients: butylated hydroxyanisole, edetate disodium dihydrate, gelatin, glycerin, hydrogenated vegetable oil, purified water, soybean oil, titanium dioxide, and white wax (beeswax).

In addition, the 10 mg capsule contains iron oxide black and iron oxide yellow. The 20 mg capsule contains iron oxide black, iron oxide red and iron oxide yellow. The 30 mg capsule contains FD&C yellow #6 aluminum lake. The 40 mg capsule contains FD&C yellow #6 aluminum lake.

Product meets USP Dissolution Test 4.

CLINICAL PHARMACOLOGY

Isotretinoin is a retinoid, which when administered in pharmacologic dosages of 0.5 to 1 mg/kg/day (see DOSAGE AND ADMINISTRATION), inhibits sebaceous gland function and keratinization. The exact mechanism of action of isotretinoin is unknown.

Nodular Acne

Clinical improvement in nodular acne patients occurs in association with a reduction in sebum secretion. The decrease in sebum secretion is temporary and is related to the dose and duration of treatment with isotretinoin, and reflects a reduction in sebaceous gland size and an inhibition of sebaceous gland differentiation.1

Pharmacokinetics

Absorption

Due to its high lipophilicity, oral absorption of isotretinoin is enhanced when given with a high fat meal. In a crossover study, 74 healthy adult subjects received a single 80 mg oral dose (2 x 40 mg capsules) of isotretinoin under fasted and fed conditions. Both peak plasma concentration (Cmax ) and the total exposure (AUC) of isotretinoin were more than doubled following a standardized high fat meal when compared with isotretinoin given under fasted conditions (see Table 2). The observed elimination half-life was unchanged. This lack of change in half-life suggests that food increases the bioavailability of isotretinoin without altering its disposition. The time to peak concentration (Tmax ) was also increased with food and may be related to a longer absorption phase. Therefore, isotretinoin capsules should always be taken with food (see DOSAGE AND ADMINISTRATION). Clinical studies have shown that there is no difference in the pharmacokinetics of isotretinoin between patients with nodular acne and healthy subjects with normal skin.

Table 2. Pharmacokinetic Parameters of Isotretinoin Mean (%CV), N = 74

Isotretinoin 2 x 40 mg Capsules

AUCo-∞

(nghr/mL)

Cmax

(ng/mL)

Tmax

(hr)

t½

(hr)

Fed*

10,004 (22%)

862 (22%)

5.3 (77%)

21 (39%)

Fasted

3,703 (46%)

301 (63%)

3.2 (56%)

21 (30%)

* Eating a standardized high fat meal


Distribution

Isotretinoin is more than 99.9% bound to plasma proteins, primarily albumin.


Metabolism

Following oral administration of isotretinoin, at least three metabolites have been identified in human plasma: 4-oxo -isotretinoin, retinoic acid (tretinoin), and 4-oxo -retinoic acid (4-oxo -tretinoin). Retinoic acid and 13-cis -retinoic acid are geometric isomers and show reversible interconversion. The administration of one isomer will give rise to the other. Isotretinoin is also irreversibly oxidized to 4-oxo -isotretinoin, which forms its geometric isomer 4-oxo -tretinoin.

After a single 80 mg oral dose of isotretinoin to 74 healthy adult subjects, concurrent administration of food increased the extent of formation of all metabolites in plasma when compared to the extent of formation under fasted conditions.

All of these metabolites possess retinoid activity that is in some in vitro models more than that of the parent isotretinoin. However, the clinical significance of these models is unknown. After multiple oral dose administration of isotretinoin to adult cystic acne patients (≥18 years), the exposure of patients to 4-oxo -isotretinoin at steady-state under fasted and fed conditions was approximately 3.4 times higher than that of isotretinoin.

In vitro studies indicate that the primary P450 isoforms involved in isotretinoin metabolism are 2C8, 2C9, 3A4 and 2B6. Isotretinoin and its metabolites are further metabolized into conjugates, which are then excreted in urine and feces.

Elimination

Following oral administration of an 80 mg dose of 14 C-isotretinoin as a liquid suspension, 14 C-activity in blood declined with a half-life of 90 hours. The metabolites of isotretinoin and any conjugates are ultimately excreted in the feces and urine in relatively equal amounts (total of 65% to 83%). After a single 80 mg oral dose of isotretinoin to 74 healthy adult subjects under fed conditions, the mean ± SD elimination half-lives (t½ ) of isotretinoin and 4-oxo -isotretinoin were 21 ± 8.2 hours and 24 ± 5.3 hours, respectively. After both single and multiple doses, the observed accumulation ratios of isotretinoin ranged from 0.9 to 5.43 in patients with cystic acne.

Special Patient Populations

Pediatric Patients

The pharmacokinetics of isotretinoin were evaluated after single and multiple doses in 38 pediatric patients (12 to 15 years) and 19 adult patients (≥ 18 years) who received isotretinoin for the treatment of severe recalcitrant nodular acne. In both age groups, 4-oxo -isotretinoin was the major metabolite; tretinoin and 4-oxo -tretinoin were also observed. The dose-normalized pharmacokinetic parameters for isotretinoin following single and multiple doses are summarized in Table 3 for pediatric patients. There were no statistically significant differences in the pharmacokinetics of isotretinoin between pediatric and adult patients.

Table 3. Pharmacokinetic Parameters of Isotretinoin Following Single and Multiple Dose Administration in Pediatric Patients, 12 to 15 Years of Age Mean (± SD), N = 38*

Parameter

Isotretinoin (Single Dose)

Isotretinoin (Steady-State)

Cmax (ng/mL)

573.25 (278.79)

731.98 (361.86)

AUC(0 to 12) (ng·hr/mL)

3033.37 (1394.17)

5082 (2184.23)

AUC(0 to 24) (ng·hr/mL)

6003.81 (2885.67)

Tmax (hr)

6 (1 to 24.6)

4 (0 to 12)

Cssmin (ng/mL)

352.32 (184.44)

T½ (hr)

15.69 (5.12)

CL/F (L/hr)

17.96 (6.27)

* The single and multiple dose data in this table were obtained following a non-standardized meal that is not

comparable to the high fat meal that was used in the study in Table 2.

Median (range)

In pediatric patients (12 to 15 years), the mean ± SD elimination half-lives (t½ ) of isotretinoin and 4-oxo -isotretinoin were 15.7 ± 5.1 hours and 23.1 ± 5.7 hours, respectively. The accumulation ratios of isotretinoin ranged from 0.46 to 3.65 for pediatric patients.

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